1. Field of the Invention
This invention relates to novel nonpeptide compounds having bradykinin antagonist activity, their pharmaceutically acceptable salts, process for their preparation, pharmaceutical compositions containing the novel nonpeptides having bradykinin antagonist activity, and method of treating diseased conditions in a mammal including inflammation, pain, irregular blood pressure and irregular smooth muscle contractility. Specifically, the invention relates to novel, nonpeptide antagonist molecules with high affinity at the human bradykinin B.sub.2 receptor.
2. Reported Developments
The nonapeptide bradykinin (Arg-Pro-Pro-Gly-Phe-Pro-Phe-Arg) Seg. ID NO. 1 is enzymatically released by kallikreins from precursor molecules (kininogens) in plasma and tissue (Proud and Kaplan, (1988) Ann. Rev. Immunol. 6:49) in response to trauma, tissue injury or activation of the kallikrein system by any means. The cellular effects of bradykinin are mediated through specific cell surface receptors (Plevin and Own, (1988) Trends, Pharmacol. Sci., 9:387). Bradykinin receptors have been initially divided into two classes, B.sub.1 and B.sub.2, based on the activity of selective receptor antagonists for the B.sub.1 receptor (Regoli and Barabe, (1980) Pharmacol. Rev. 32(1):1). Bradykinin activation of bradykinin receptors leads to intracellular signalling events resulting in the activation of the arachidonic acid cascade to produce prostaglandins and leukotrienes.
Bradykinin is released in the early stages following tissue injury and possesses several properties which implicate its role in the inflammatory events of rheumatoid arthritis. These include the ability to: (a) induce vasodilation; (b) enhance vascular permeability; (c) induce pain; and (d) induce synthesis and release of arachidonic acid metabolites. Bradykinin has been demonstrated to play a role in a variety of physiological functions including pain, inflammation, regulations of blood pressure and smooth muscle contractility (Rocha e Silva et al, (1949) Am. J. Physiol. 156:261; Regoli, (1983) Adv. Exp. Med, Biol. 156A:569). Examples and literature references include the following:
Bradykinin is one of the most potent pain producing substances (Collier et al, (1963) Br. J. Pharmacol. 21:151). The application of bradykinin to the free nerve endings of a blister base in humans has been shown to produce pain (Armstrong et al, (1957) J. Physiol. 135:350). The intraperitoneal or intraarterial administration of bradykinin has also been shown to produce pain in man. The production of pain in humans or the demonstration of hyperalgesia in experimental animals occurs primarily in association with an inflammatory component. Increased levels of circulating bradykinin have been demonstrated in acute (oral surgery) and chronic (rheumatoid arthritis) inflammatory states (Hargreaves et al., (1988) Clinical Pharmacology & Therapeutics, 44:163).
Bradykinin antagonists (substituted bradykinin peptide analogues) have been shown to be anti-inflammatory as well as antinociceptive. The inflammation and hyperalgesia produced by the intraplantar injection of carrageenan has been shown to be antagonized by NPC-567 (Costello and Hargreaves, (1989) European J. Pharmacol., 171:259; Burch and DeHaas, (1990) N. S. Arch. Pharmacol., 342:189). Steranka et al, (1988; Proc. Natl. Acad. Sci., 85:3245) have demonstrated that NPC-567 and NPC-349 are antinociceptive in several different animal models of nociception/hyperalgesia. In humans, the pain produced by the application of bradykinin to a blister base was also antagonized by B.sub.2 selective antagonists (Whalley et al, (1987) Naunyn-Schmeid. Arch. Pharmacol. 336:652).
Bradykinin is one of the primary mediators in the production of the inflammatory response. Bradykinin ilicits all of the cardinal signs of inflammation and has been identified in inflammatory exudates (Marceau et al, (1983) Gen. Pharmacol. 14:209). Synovial fluids from patients with rheumatoid arthritis, gout and psoriatic arthritis have been shown to contain elevated kinin levels (Jasani et al, (1969) Ann. Rheum. Dis. 28:497), whereas lower levels were reported from non-inflammatory joints (Eisen, V. (1970) Br. J. Exp. Pathol. 51:322). Intra-articular injection of bradykinin into dogs has been shown to cause an acute inflammatory response (Lerner et al, (1987) Arth. Rheum. 30:530). Bradykinin has been reported to stimulate the production of prostacyclin and PGE.sub.2, known mediators in inflammation, from fibroblasts and endothelial cells (Bareis et al, (1983) Proc. Natl. Acad. Sci. 80:2514; Leikauf et al, (1985) Am. J. Physiol. 248:48). Recently bradykinin was shown to modulate the IL-1 induced release of PGE.sub.2 from human synovial fibroblasts (Bathon et al, (1989) J. Immunol. 143:579). It has also been reported that human synovial fibroblasts from rheumatoid arthritis patients express bradykinin receptors and that following binding, bradykinin stimulates the production of PGE.sub.2 (Uhl et al, (1992) Immunopharm. 23:131). In addition, bone resorption and matrix degradation have been demonstrated with bradykinin (Lerner et al, (1987) Arth. Rheumat. 30:530).
Bradykinin has been postulated to be a mediator of upper airway disease and asthma (Farmer, (1991) Bradykinin Antagonists: Basic and Clinical Research, R. M. Burch Edt., 213). Bradykinin is very potent at producing bronchoconstriction in asthmatics (Herxheimer and Stresemann, J. Physiol., 158:38P). Bradykinin is also postulated to be involved in rhinoviral infections since it has been shown that subjects who become infected and symptomatic show increased kinin levels in nasal lavages (Naclerio et al, (1988) J. Inf. Dis. 157:133; Proud et al, (1990) J. Inf. Dis., 161:120). Furthermore, it has been demonstrated that nasal provocation with bradykinin induces symptoms of rhinitis and a sore throat (Proud et al, (1988) Am. Rev. Respir.. Dis., 137:613). A study of the intranasal bradykinin antagonist NPC-567, however, failed to demonstrate beneficial effects on the course of an experimentally induced rhinovirus infection (Bernstein et al, (1990) Antiviral Res. Suppl. 1:119). The reasons for the apparent inactivity of this compound are unknown and could reflect problems with drug delivery or metabolism.
Bradykinin, acting through specific cell surface receptors on endothelial cells, is one of the most potent agents that induces vasodilation and plasma extravisation (Regoli and Barabe, (1980) Pharmacol. Rev., 32(1):1). These physiological effects may lead to exacerbation of pathophyisological states associated with shock, ischemia secondary to head trauma, and tumor metastasis.
There is significant evidence in the literature that activation of the kinin/kallikrein cascade is associated with endotoxin mediated shock (Aasen et al (1983) Arch. Surg., 118:343; Katori et al, (1989) Br. J. Pharmcol. 98"1381). The evidence for this includes 1) elevated levels of free bradykinin and enhanced plasma kallikrein activity in plasma treated with endotoxin; 2) endotoxin-induced dose-dependent decreases in blood pressure parallel the increase in free plasma kinin levels and the decrease in plasma HMW kininogen; and 3) attenuation of the hypotensive response and increased bradykinin levels by soybean trypsin inhibitor. Recent studies have demonstrated that the hypotensive responses and even the mortality associated with endotoxin-induced sepsis in the rat is dramatically reduced by bradykinin peptide antagonists (Weipert et al (1988) Br. J. Pharmacol. 94:282; Wilson et al (1989) Circulatory Shock, 27:93).
Ischemic brain damage occurring soon after head trauma is believed to be mediated largely by increases in intra-cranial pressure resulting from edema caused by plasma extravisation at or near the site of injury. Cerebral administration of bradykinin to rats (Kamiya, (1990) Nippon Ika Daigaku Zasshi, 57(2):180) or dogs (Unterberg and Baethmann, (1984) J. Neurosurg., 61:87) induces cerebral edema. Enhancement of plasma kinin levels (5-10 fold over control) has been demonstrated during the reperfusion period following a 3-hour ischemic insult in rats (Kamiya, (1990) Nippon Ika Daigaku Zasshi, 57(2):180). This suggests that formation of kinins may be enhanced when cerebral blood flow becomes compromised by an increase in intra-cranial pressure.
Bradykinin has demonstrated mitogenic activity in some cell lines. Roberts and Gullick (1989) J. Cell Sci., 94:527) have proposed a model in which the production of bradykinin by reactive inflammatory cells within tumors or the production of bradykinin during disruption of blood vessels may provide a paracrine stimulation of the growth of tumors expressing mutant ras oncogene with increased sensitivity to bradykinin. This stimulation may promote both tumor growth and speed. Recently significantly elevated levels of bradykinin in ascitic fluid from human cervical carcinoma and gastric carcinoma solid tumors has been observed providing further support for a role for bradykinin in metastatic disease syndromes.
There appears to be sufficient circumstantial evidence to suggest that bradykinin plays a role in irritable bowel syndrome. Kinin levels in patients with inflammatory bowel disease correlate well with the onset of vasomotor and gastrointestinal symptoms (1964; Lancet i 514-517; (1966) Lancet ii 986-991; (1971) Br. Med. J., 3:565-566; (1974) Annls. Int. Med. 80:577-581). Inflamed intestinal tissue from patients with ulcerative colitis shown high kallikrein levels (Gut (1978) 14:133-138). Bradykinin has been shown to affect gut motility (Regoli and Barabe, (1980) Pharmacol. Rev. 32:1) and bradykinin receptors have been shown to mediate a chloride secretion form the intestinal serosa to the mucosa, but apparently not in the reverse direction. (Nature (1982) 299:256-259). Most cases of clinical diarrhea are due to ion and fluid secretion into the lumen, not altered gut motility. (Pathologic Physiology: Mechanisms of Disease, (1974) Sodeman and Sodeman, Eds.; 767-789. W. B. Saunders, Philadelphia).
Stewart and Vavrek (1985), Peptides, 6:161; U.S. Pat. No. 4,693,993, issued Sep. 15,1987) describes the first bradykinin B.sub.2 peptide antagonists. The critical substitution involves the replacement of the L-proline residue in the number 7 position with an amino acid in the D-configuration; most specifically D-phenylalanine. These modified peptides have antagonist activity in a variety of assay systems (Stewart and Vavrek (1990) J. Cardiovasc. Pharmacol. 15 (Suppl. 6):S69), but also display agonist activity (Sawutz et al, (1992) Eur. J. Pharmacol., 227:309). The compounds promote mast cell degranulation (Devillier et al, (1988) Eur. J. Pharmacol, 149:137) and are rapidly cleaved at several positions, including the 8-9 bond, which significantly decreases their receptor binding activity. Replacement of arginyl residues at positions 1 and 9 in addition to N-terminal and specific C-terminal extensions, results in increased enzyme resistance and antagonist potency (Stewart et al, International Patent Applications Nos. PCT/US88/02959 and PCT/US88/02960; issued Mar. 9, 1989).
In two recent patents by Henke et al (EP 0 413 277 A1; Feb. 20,1991) and by Nestor et al (EP 0 472 220 A1; Feb 26, 1992), key replacements of Pro.sup.7 by 1,2,3,4-tetahydroisoquinoline-3-carboxylic acid (Tic) and Phe.sup.8 by octahydroindole-2-carboxylic acid (Oic) resulted in novel bradykinin peptide antagonists. These, and other changes, resulted in compounds with significantly increased potency at the bradykinin receptor (approximately 2 orders of magnitude compared to D-Phe.sup.7 !-bradykinin) and greater metabolic stability.
It is an object of this invention to provide bradykinin receptor antagonists of a nonpeptide nature having high potency at the human bradykinin B.sub.2 receptor. These advantages are demonstrated in recognized assays in which compounds of this invention exhibit high potency. This invention encompasses methods for preparing the compounds of the invention, including pharmaceutically acceptable salts, and therapeutic uses for compounds of this invention. Furthermore, this invention provides compositions for treatment of an individual wherein the pharmaceutical compositions comprises an effective amount of a compound of the invention and a compatible pharmaceutically acceptable carrier.